The overall hypothesis that underlies the focus of this grant proposal is that chronic TH1/classical inflammation is critical for the progression of neurodegeneration in Parkinson's disease (PD) and Gulf War Illnesses (GWI) and other neurodegenerative diseases. There is strong evidence from the literature that inflammation and oxidative damage are observed in the brains of PD patients, GWI patients and patients with other neurodegenerative diseases. Furthermore, there is mounting evidence that an imbalance of TH1/classical vs TH2/alternative inflammatory mechanisms is involved in the progression of many immunologically mediated degenerative diseases, and that aging is a predisposing factor for the imbalance of TH1/TH2. It is our hypothesis that increased TH1/classical immune activation via the innate immune system is responsible for ongoing neurodegeneration and that switching the immune balance toward a TH2/alternative profile will slow the progression of neurodegeneration. The aims of this proposal are designed to examine this process by following the progression of damage from wild-type (WT) alpha-synuclein overexpressed in neurons of the substantia nigra via transduction with adeno-associated virus (AAV) 9. In this model, low expression of AAV9-WT alpha-synuclein induces a progressive loss of DA neurons over a period of 6 or more months making it an ideal model to study the neurodegenerative process. We will study the role of inflammation in this model and using several model systems to either increase or decrease the TH1/classical and TH2/alternative innate immune response to WT alpha-synuclein. Specific Aim 1. Hypothesis: Increasing TH1 microglial cytokine production by reducing CX3CR1 will lead to increased vulnerability to 1-synuclein. We will use a blocking antibody to the fractalkine receptor in rats as well as fractalkine receptor knockout mice to address this question. Specific Aim 2. Hypothesis: Pushing inflammation towards TH2/alternative activation will diminish neurodegeneration from rAAV9-1-synuclein or MPTP. We will use fractalkine as a therapeutic approach in rats as well as a T-bet knockout mouse. Specific Aim 3. Hypothesis: Aging is a significant predisposing factor to neurodegenerative disease because of the imbalance between TH1/TH2 immune pathways. Switching the balance with drugs that block Tbet will be useful treatments for PD and other neurodegenerative diseases. This will be examined in young and aged rats to examine 2 aspects of this process. First will drugs that block T-bet be useful in a either young or aged rats with AAV-synuclein lesions and the second question is if the aging process will be additive in the progression of the lesion. PUBLIC HEALTH RELEVANCE: Potential Impact on Veterans Health Care. There is ample evidence that Parkinson's disease is a major debilitating disease that effects many veterans. This disorder and related Parkinsonian signs are associated with a significant risk of morbidity and mortality in elderly veterans. Furthermore, Gulf War Illness (GWI) has been associated with a similar phenotype and loss of dopamine cells in the substantia nigra. This set of neurodegenerative diseases impacts veteran's ability to locomote as one of the main symptoms is bradykinesia. It also decreases a veteran's ability to carry out normal tasks of daily living as the disease progresses and becomes more debilitating. If we can understand the basis of this neurodegenerative process then we can design appropriate pharmacological therapies for intervention such as drugs that interfere with the balance of TH1/classical and TH2/alternative activation states. If these therapies have significant clinical potential this will be a step forward for Parkinsons therapeutics.